Targeting Oncofetal Fibronectin and Neuropilin-1 in solid tumors with PL2 peptide

Abstract To improve the precision and selectivity of anticancer therapies, affinity ligands targeting molecules of the malignancy-associated vascular signature are used. One such target is Fibronectin Extra Domain-B (Fn-EDB), an oncofetal splice variant of a major extracellular matrix protein (Fn), which is upregulated in many solid tumors as part of the angiogenic response. In this study, we conducted cell-free biopanning on recombinant Fn-EDB to identify a short peptide designated as PL2 (amino acid sequence: TSKQNSR), which specifically interacts with Fn-EDB. Notably, the C-terminal arginine of PL2 enables its interaction with neuropilin-1 (NRP-1), a receptor known to facilitate cell and tissue penetration. When administered systemically, PL2-displaying recombinant bacteriophages and iron oxide nanoworms (NWs) functionalized with PL2 peptide exhibited homing to glioblastoma and prostate tumor xenografts, followed by their extravasation and penetration into tumor parenchyma. Notably, PL2-functionalized NWs penetrated ex vivo explants of clinical ovarian carcinoma, underscoring their translational potential. These findings underscore the potential of the PL2 peptide as a promising agent for anticancer drug delivery and molecular imaging applications. One Sentence Summary: PL2 tumor penetrating peptide targeting Fibronectin Extra Domain-B (Fn-EDB) and Neuropilin-1 (NRP-1) can be used for precision delivery of payloads to the microenvironment of solid tumors